Institute of Cancer Stem Cells, Dalian Medical University, Dalian 116044, China.
Dalian Municipal Central Hospital, Dalian University of Technology, Dalian 116044, China.
Biomolecules. 2024 Jun 23;14(7):741. doi: 10.3390/biom14070741.
As a kind of proteolytic enzyme extracted from , lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.
作为一种从地龙中提取的蛋白水解酶，蚓激酶已在临床上用作抗血栓药物。然而，其在抗癌方面的潜力，特别是作为单一形式的治疗或与其他疗法联合治疗非小细胞肺癌（NSCLC）的潜力，仍知之甚少。在这项研究中，我们探讨了蚓激酶抑制肿瘤血管生成和化疗耐药发展的抗肿瘤作用和响应分子机制，及其与贝伐珠单抗和化疗联合治疗 NSCLC 的临床潜力。蚓激酶被发现以浓度依赖的方式抑制细胞增殖，并在不同程度上抑制 NSCLC 细胞的转移和诱导凋亡。蚓激酶通过下调 BPTF 的表达，降低其在 启动子区域的锚定及其随后的 VEGF 表达和分泌，增强了贝伐珠单抗的抗血管生成效率。此外，蚓激酶通过使 NF-κB 通路失活，抑制 COX-2 的表达及其随后 PGE2 的分泌，降低了亲本和化疗耐药 NSCLC 细胞中化疗药物的 IC50 值并提高了其细胞毒性。LPS 诱导的 NF-κB 激活逆转了其对 NSCLC 细胞增殖的抑制及其与化疗药物协同的细胞毒性，而 COX-2 抑制剂塞来昔布的处理则增强了这种作用。蚓激酶联合贝伐珠单抗、紫杉醇或长春新碱抑制了 NSCLC 细胞在小鼠中的异种移植生长，其效果比单一治疗更为显著。总之，蚓激酶通过靶向下调 BPTF/VEGF 信号和失活 NF-κB/COX-2 信号，抑制 NSCLC 的存活并使 NSCLC 细胞对贝伐珠单抗或化疗药物治疗敏感。蚓激酶与贝伐珠单抗或化疗药物的联合应用有望被开发为提高原单一治疗抗 NSCLC 疗效的有前途的候选治疗策略。
